Abstract Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of T lymphocytes malignancies that primarily affect skin. Mycosis fungoides (MF) is the most common form of CTCL and typically runs an indolent course. However, in a significant number of patients the disease may progress and tumor cells spread to other sites of the body leading to a fatal outcome. Diagnosis of MF, especially in the early stages, is difficult to establish due to the absence of specific markers for malignant lymphocytes. Limited treatment options are available for patients with advanced-stage MF, a reflection of the poor understanding of disease pathogenesis. We have recently demonstrated that IL-13 and its receptors represent novel markers of malignancy in MF. Our studies further implicated IL-13 signaling via the Signal Transducer and Activator of Transcription-6 (STAT-6) protein. Significantly, we found high numbers of activated STAT-6+ cells in the affected skin of MF patients, particularly in advanced stages. Here we propose to analyze the molecular pathways of IL-13 signaling in malignant cells from aggressive forms of MF. Our central hypothesis is that STAT-6 is a major factor in the pathogenesis of MF that is critical in promoting disease progression and represents a potential target for therapy. The Specific Aims of this proposal are based solidly on our previous results and focus on identifying the unique role of STAT-6 in the pathogenesis of MF, thus shedding light on the molecular mechanisms underlying IL-13-induced tumor cell proliferation in MF. Identifying the mechanisms of MF pathogenesis will reveal novel diagnostic agents and molecular targets, leading to innovative therapies against this disease.